(PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy

Total Page:16

File Type:pdf, Size:1020Kb

(PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy CLINICAL RESEARCH www.jasn.org Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy † ‡ Marieke J.H. Coenen,* Julia M. Hofstra, Hanna Debiec, Horia C. Stanescu,§ | Alan J. Medlar,§ Bénédicte Stengel, ¶ Anne Boland-Augé,** Johanne M. Groothuismink,* †† ‡‡ Detlef Bockenhauer,§ Steve H. Powis,§ Peter W. Mathieson, Paul E. Brenchley, † ‡ Robert Kleta,§ Jack F.M. Wetzels, and Pierre Ronco *Department of Human Genetics and †Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; ‡Institut National de la Santé et de la Recherche Médicale, Université Pierre et Marie Curie Univ-Paris, Assistance Publique-Hôpitaux de Paris, Department of Nephrology, Tenon Hospital, Paris, France; §Centre for Nephrology, University College London, London, United Kingdom; |Institut National de la Santé et de la Recherche Médicale U1018, CESP, Team 10, Villejuif, France; ¶Université Paris-Sud, Villejuif, France; **Centre National de Génotypage, Institut de Génomique CEA, Evry, France; ††Academic Renal Unit, University of Bristol, Bristol, United Kingdom; and ‡‡School of Biomedicine, University of Manchester, Manchester, United Kingdom ABSTRACT The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA- DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 se- quence variants, comprising 2 not previously described, 7 reported as rare variants (,1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymor- phisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN. J Am Soc Nephrol 24: 677–683, 2013. doi: 10.1681/ASN.2012070730 Idiopathic membranous nephropathy (iMN) is the established that 70% of white patients with active leading cause of nephrotic syndrome in the adult disease have antibodies against PLA2R1.1,3,4 white population. It is characterized by immune complex deposition in the subepithelial layer of the glomerular basement membrane. On the basis of Received July 25, 2012. Accepted December 5, 2012. studies in Heymann nephritis, a model of MN in the M.J.H.C., J.M.H., and H.D. contributed equally to this work; R.K., rat, it was suggested that immune complexes were J.F.M.W., and P.R. contributed equally to this work formed locally, by the binding of antibodies to a Published online ahead of print. Publication date available at 1 podocytic antigen. The description of neonatal www.jasn.org. MN caused by maternal antibodies against neutral Correspondence: Dr. Marieke Coenen, Department of Human 2 endopeptidase provided proof of concept. Further Genetics, Radboud University Nijmegen Medical Centre, PO Box evidence was provided by the discovery of the 9101, 6500 HB Nijmegen, The Netherlands. Email: m.coenen@ M-type receptor for phospholipase A2 (PLA2R1) as gen.umcn.nl the predominant autoantigen in iMN.3 It is well Copyright © 2013 by the American Society of Nephrology J Am Soc Nephrol 24: 677–683, 2013 ISSN : 1046-6673/2404-677 677 CLINICAL RESEARCH www.jasn.org Although no studies have firmly proven that the antibodies are these rare variants (rs141800672, rs149256089, rs150221555, indeed pathogenic, genetics studies have supported the impor- rs140427239, rs149960520, rs149133741, and rs181959329) tant role of PLA2R1 in the pathogenesis of iMN. Recently, we have been reported in publicly available data sets with very have shown highly significant associations to iMN with single low minor allele frequencies (#0.2%). We identified two nucleotide polymorphisms (SNPs) located on chromosomes 6 novel missense variants that have not been previously reported, and 2, by means of genome-wide association studies (GWAS) which result in amino acid changes (c.1160G.A, p.Arg387His; in three independent cohorts.5 The region of interest defined c.2060T.C, p.Leu687Pro). The novel variant c.1160G.A, on chromosome 2 includes the gene PLA2R1. SNPs in this gene p.Arg387His and the splice site change c.3850+1G.A (IVS26 have also been shown to be associated to iMN susceptibility in +1G.A) (rs181959329) were carried by the same patient. two candidate gene association studies performed in Korea and Additionally, nine common SNPs were observed; six of them Taiwan.6,7 These findings together suggest an important role for in the coding regions (rs4665143, rs3749117, rs35771982, PLA2R1 in the pathogenicity of iMN. rs33985939, rs72954858, and rs3828323) and three in noncod- Our GWAS was based on common SNPs, as is typical for ing regions (rs2715918, rs925409, and rs3749119). most GWAS. These SNPs serve as genetic markers used to In the subgroup of 60 anti-PLA2R-positive patients, four identify alleles or haplotypes of interest. Of note, our GWAS of the rare variants (rs149256089, rs140427239, rs149960520, study showed that both the HLA locus on chromosome 6 and and rs149133741) were each observed once in four different the PLA2R1 locus on chromosome 2 were significantly asso- patients. The two novel variants were not observed in this ciated with iMN not only on the SNP level (basic allele test) subgroup (Table 2). but also on the haplotype level (haplotype association test).5 Of the 15 observed coding variants, 12 (rs149133741, These SNPs demarcate alleles that are different in cases versus rs149960520, rs140427239, rs33985939, rs150221555, controls. Not only common SNPs but also rare mutations can rs35771982, rs3749117, rs149256089, rs141800672, rs4665143, be the cause of a signal identified by GWAS.8 Although iMN is and the novel p.Arg387His and p.Leu687Pro) are located with- not a simple genetic disorder with classic Mendelian inheri- in the regions coding for known domains of PLA2R1, of which 1 tance, the strong and significant association of this phenotype (rs3749117) is located within the WMGL motif of the C-type to PLA2R1 (and the HLA locus) leads to the hypothesis that lectin-like domain (CTLD)-1 of PLA2R1. Two other coding rare genetic variants within the coding region of the PLA2R1 variants, one common (rs33985939, p.Arg404His) and one rare gene may explain antibody formation. In the current study, we (rs140427239, p.Tyr499Cys), are situated one and two amino performed sequencing of the coding regions of the PLA2R1 acids, respectively, away from the cysteine residues involved in gene to confirm this hypothesis. disulfide bond formation (C4 and C1 in CTLD2; see Table 1 and Figure 1). The essential splice site at the border between exon 26 and RESULTS intron 26 is altered in one patient, c.3850+1G.A(IVS26 +1G.A) (rs181959329), predicted to lead to exon 26 being Patient Characteristics skipped, which is in frame. This leads to a shortened PLA2R1 Ninety-five patients with biopsy-proven iMN were included: protein missing 46 amino acids within CTLD8, obliterating 48 from the French cohort and 47 from the Dutch cohort, the first cysteine residue involved in disulfide bond formation respectively. Patients were mostly male (75%), and the mean (C1). Of note, this is a known sequence variant with a yet un- age 6 SD at diagnosis was 51615 years. All patients were of determined allele frequency in the general population. self-reported white ancestry. Of note, Single Nucleotide Polymorphism Database release Serum samples were available for 82 patients; anti-PLA2R 136 (February 2012) currently has 138 human sequence variants antibodies were present in 43 samples. In addition, 17 patients curated within the coding region, including splice sites of were considered positive according to the presence of PLA2R PLA2R1. Actually, only 8 of the 138 variants are frequently ob- antigenintheirkidneybiopsyspecimen(SupplementalTableS1). served, nonsynonymous, coding variants. Minor allele frequen- cies were not established for most of those SNPs. Sequencing All 30 exons, including essential splice sites (defined as the two Association intronic nucleotides—canonical GT and AG—at the intron- The common SNPs identified by our sequencing permit us to exon boundaries, respectively) were sequenced by Sanger tech- analyze the PLA2R1 region in more detail compared with the nology. We identified 18 variants, including 3 in noncoding GWAS that mainly included common intronic SNPs (typical regions (Table 1). for SNP chips used for GWAS). Of the 18 variants observed, 9 were rare or novel (see the In the 95 patients with iMN studied, the allele frequency of Concise Methods section for definitions). These 9 variants several SNPs was significantly different from that of the ethni- were all encountered in a heterozygous state in one patient cally matched controls from the 1000 Genomes project (see each, except for the rare variant rs149133741 (c.2038G.T, Table 1). Specifically, there was a significant difference for
Recommended publications
  • Functional Classification of 15 Million Snps Detected from Diverse
    DNA Research, 2015, 22(3), 205–217 doi: 10.1093/dnares/dsv005 Advance Access Publication Date: 29 April 2015 Full Paper Full Paper Functional classification of 15 million SNPs detected from diverse chicken populations Almas A. Gheyas*, Clarissa Boschiero†, Lel Eory, Hannah Ralph, Richard Kuo, John A. Woolliams, and David W. Burt* The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK *To whom correspondence should be addressed. Tel. +44 (0)131-651-9216. Fax. +44 (0)131-651-9105. E-mail: dave.burt@roslin. ed.ac.uk (D.W.B.); Tel. +44(0)131-651-9100. Fax. +44(0)131-651-9105. E-mail: [email protected] (A.A.G.) †Current Address: USP/ESALQ, Dept. de Zootecnia, Piracicaba, SP 13418-900, Brazil. Edited by Dr Toshihiko Shiroishi Received 30 January 2015; Accepted 20 March 2015 Abstract Next-generation sequencing has prompted a surge of discovery of millions of genetic variants from vertebrate genomes. Besides applications in genetic association and linkage studies, a fraction of these variants will have functional consequences. This study describes detection and characteriza- tion of 15 million SNPs from chicken genome with the goal to predict variants with potential function- al implications (pfVars) from both coding and non-coding regions. The study reports: 183K amino acid-altering SNPs of which 48% predicted as evolutionary intolerant, 13K splicing variants, 51K like- ly to alter RNA secondary structures, 500K within most conserved elements and 3K from non-coding RNAs. Regions of local fixation within commercial broiler and layer lines were investigated as poten- tial selective sweeps using genome-wide SNP data.
    [Show full text]
  • PLA2R1) Zoya Khalid1* & Omar Almaghrabi2
    www.nature.com/scientificreports OPEN Mutational analysis on predicting the impact of high‑risk SNPs in human secretary phospholipase A2 receptor (PLA2R1) Zoya Khalid1* & Omar Almaghrabi2 PLA2R1 is a transmembrane glycoprotein that acts as an endogenous ligand which stimulates the processes including cell proliferation and cell migration. The SNPs in PLA2R1 is associated with idiopathic membranous nephropathy which is an autoimmune kidney disorder. The present study aimed to explore the structure–function analysis of high risk SNPs in PLA2R1 by using 12 diferent computational tools. First the functional annotation of SNPs were carried out by sequence based tools which were further subjected to evolutionary conservation analysis. Those SNPs which were predicted as deleterious in both categories were further considered for structure based analysis. The resultant SNPs were C1096S, C545S, C664S, F1257L, F734S, I1174T, I1114T, P177S, P384S, W1198G, W1328G, W692C, W692L, W962R, Y499H. One functional domain of PLA2R1 is already modelled in PDB (6JLI), the full 3D structure of the protein was predicted using I-TASSER homology modelling tool. The stability analysis, structure superimposition, RMSD calculation and docking studies were carried out. The structural analysis predicted four mutations F734S, F1246L, I1174T, W1198G as damaging to the structure of the protein. All these mutations are occurring at the conserved region of CTL domain hence are more likely to abolish the function of the protein. Up to the best of our knowledge, this is the frst study that provides in-depth and in-silico analysis of deleterious mutations on structure and function of PLA2R1. Phospholipases play a vital role in many cellular processes including phospholipids digestion and metabolism.
    [Show full text]
  • Long Non-Coding Rnas and Micrornas in Endocrine-Related Cancers
    25 4 Endocrine-Related C M Klinge lncRNAs and miRNAs in 25:4 R259–R282 Cancer endocrine-related cancers REVIEW Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers Carolyn M Klinge Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA Correspondence should be addressed to C M Klinge: [email protected] Abstract The human genome is ‘pervasively transcribed’ leading to a complex array of non- Key Words coding RNAs (ncRNAs) that far outnumber coding mRNAs. ncRNAs have regulatory roles f miRNA in transcription and post-transcriptional processes as well numerous cellular functions f lncRNA that remain to be fully described. Best characterized of the ‘expanding universe’ of f ncRNA ncRNAs are the ~22 nucleotide microRNAs (miRNAs) that base-pair to target mRNA’s f transcription 3′ untranslated region within the RNA-induced silencing complex (RISC) and block f translation translation and may stimulate mRNA transcript degradation. Long non-coding RNAs (lncRNAs) are classified as >200 nucleotides in length, but range up to several kb and are heterogeneous in genomic origin and function. lncRNAs fold into structures that interact with DNA, RNA and proteins to regulate chromatin dynamics, protein complex assembly, transcription, telomere biology and splicing. Some lncRNAs act as sponges for miRNAs and decoys for proteins. Nuclear-encoded lncRNAs can be taken up by mitochondria and lncRNAs are transcribed from mtDNA. Both miRNAs and lncRNAs are dysregulated in endocrine cancers. This review provides an overview on the current understanding of the regulation and function of selected lncRNAs and miRNAs, and their interaction, in Endocrine-Related Cancer endocrine-related cancers: breast, prostate, endometrial and thyroid.
    [Show full text]
  • The Draft Genome Sequence of the Ferret (Mustela Putorius Furo) Facilitates Study of Human Respiratory Disease
    LETTERS OPEN The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease Xinxia Peng1, Jessica Alföldi2, Kevin Gori3, Amie J Eisfeld4, Scott R Tyler5,6, Jennifer Tisoncik-Go1, David Brawand2,22, G Lynn Law1, Nives Skunca7,8, Masato Hatta4, David J Gasper4, Sara M Kelly1, Jean Chang1, Matthew J Thomas1, Jeremy Johnson2, Aaron M Berlin2, Marcia Lara2,22, Pamela Russell2,22, Ross Swofford2, Jason Turner-Maier2, Sarah Young2, Thibaut Hourlier9, Bronwen Aken9, Steve Searle9, Xingshen Sun5, Yaling Yi5, M Suresh4, Terrence M Tumpey10, Adam Siepel11, Samantha M Wisely12, Christophe Dessimoz3,13,14, Yoshihiro Kawaoka4,15–18, Bruce W Birren2, Kerstin Lindblad-Toh2,19, Federica Di Palma2,22, John F Engelhardt5,20, Robert E Palermo1 & Michael G Katze1,21 The domestic ferret (Mustela putorius furo) is an important gaps, has a contig N50 size of 44.8 kb, a scaffold N50 size of 9.3 Mb animal model for multiple human respiratory diseases. It is and quality metrics comparable to other genomes sequenced using considered the ‘gold standard’ for modeling human influenza Illumina technology (Table 1 and Supplementary Note). RNA-seq virus infection and transmission1–4. Here we describe the data for annotation were obtained from polyadenylated transcripts 2.41 Gb draft genome assembly of the domestic ferret, using RNA from 24 samples of 21 tissues from male and female fer- constituting 2.28 Gb of sequence plus gaps. We annotated rets, including both developmental and adult tissues (Supplementary 19,910 protein-coding genes on this assembly using RNA- Table 1). The genome assembly was annotated using the Ensembl seq data from 21 ferret tissues.
    [Show full text]
  • Transcriptomic Analysis of Breast Cancer Patients Sensitive and Resistant to Chemotherapy: Looking for Overall Survival and Drug Resistance Biomarkers
    Transcriptomic analysis of breast cancer patients sensitive and resistant to chemotherapy: Looking for overall survival and drug resistance biomarkers Carlos Barrón-Gallardo University of Guadalajara Mariel García-Chagollán University of Guadalajara Andrés Morán-Mendoza Mexican Social Security Institute Raúl Delgadillo-Cristerna Mexican Social Security Institute María Martínez-Silva Mexican Social Security Institute Adriana Aguilar-Lemarroy Mexican Social Security Institute Luis Jave-Suárez ( [email protected] ) Mexican Social Security Institute Research Article Keywords: breast cancer patients, neoadjuvant chemotherapy, resistance development, differentially expressed genes (DEGs), chemotherapy response, overall survival Posted Date: December 15th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-121509/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/26 Abstract Neoadjuvant chemotherapy is one important therapeutic strategy for breast cancer with the drawback of resistance development. Chemotherapy has adverse effects that combined with resistance could contribute to lower overall survival. This work aimed to evaluate the molecular prole of patients who received neoadjuvant chemotherapy to discover differentially expressed genes (DEGs) that could be used as biomarkers of chemotherapy response and overall survival. Breast cancer patients who received neoadjuvant chemotherapy were enrolled in this study and according to their pathological response were assigned as sensitive or resistant. To evaluate DEGs, GO, KEGG, and protein-protein interactions, RNAseq information from all patients was obtained by next-generation sequencing. A total of 1985 DEGs were found and KEGG analysis indicated a great number of DEGs in metabolic pathways, pathways in cancer, cytokine-cytokine receptor interactions, and neuroactive ligand-receptor interactions.
    [Show full text]
  • DNA Res-2015-Gheyas-Dnares-Dsv005
    Edinburgh Research Explorer Functional classification of 15 million SNPs detected from diverse chicken populations Citation for published version: Gheyas, AA, Boschiero, C, Eory, L, Ralph, H, Kuo, R, Woolliams, JA & Burt, DW 2015, 'Functional classification of 15 million SNPs detected from diverse chicken populations', DNA Research, vol. 22, no. 3, pp. 205-217. https://doi.org/10.1093/dnares/dsv005 Digital Object Identifier (DOI): 10.1093/dnares/dsv005 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: DNA Research General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 28. Sep. 2021 DNA Research Advance Access published April 29, 2015 DNA Research, 2015, 1–13 doi: 10.1093/dnares/dsv005 Full Paper Full Paper Functional classification of 15 million SNPs detected from diverse chicken populations Almas A. Gheyas*, Clarissa Boschiero†, Lel Eory, Hannah Ralph, Richard Kuo, John A. Woolliams, and David W. Burt* The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Downloaded from Midlothian EH25 9RG, UK *To whom correspondence should be addressed.
    [Show full text]
  • Bioinformatics Analysis of Potential Key Genes and Mechanisms in Type 2 Diabetes Mellitus Basavaraj Vastrad1, Chanabasayya Vastrad*2
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.28.437386; this version posted May 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2021.03.28.437386; this version posted May 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Type 2 diabetes mellitus (T2DM) is etiologically related to metabolic disorder. The aim of our study was to screen out candidate genes of T2DM and to elucidate the underlying molecular mechanisms by bioinformatics methods. Expression profiling by high throughput sequencing data of GSE154126 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between T2DM and normal control were identified. And then, functional enrichment analyses of gene ontology (GO) and REACTOME pathway analysis was performed. Protein–protein interaction (PPI) network and module analyses were performed based on the DEGs. Additionally, potential miRNAs of hub genes were predicted by miRNet database . Transcription factors (TFs) of hub genes were detected by NetworkAnalyst database. Further, validations were performed by receiver operating characteristic curve (ROC) analysis and real-time polymerase chain reaction (RT-PCR).
    [Show full text]
  • The Timing of Human Adaptation from Neanderthal Introgression
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.04.325183; this version posted March 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. The timing of human adaptation from Neanderthal introgression Sivan Yair1;2, Kristin M. Lee3 and Graham Coop1;2 1 Center for Population Biology, University of California, Davis. 2 Department of Evolution and Ecology, University of California, Davis 3 Previous address: Department of Biological Sciences, Columbia University To whom correspondence should be addressed: [email protected] 1 Abstract 2 Admixture has the potential to facilitate adaptation by providing alleles that are immediately adaptive in a 3 new environment or by simply increasing the long term reservoir of genetic diversity for future adaptation. 4 A growing number of cases of adaptive introgression are being identified in species across the tree of life, 5 however the timing of selection, and therefore the importance of the different evolutionary roles of admixture, 6 is typically unknown. Here, we investigate the spatio-temporal history of selection favoring Neanderthal- 7 introgressed alleles in modern human populations. Using both ancient and present-day samples of modern 8 humans, we integrate the known demographic history of populations, namely population divergence and 9 migration, with tests for selection. We model how a sweep placed along different branches of an admixture 10 graph acts to modify the variance and covariance in neutral allele frequencies among populations at linked 11 loci.
    [Show full text]
  • Towards Retinal Repair: Analysis of Photoreceptor Precursor Cells and Their Cell Surface Molecules
    Towards retinal repair: analysis of photoreceptor precursor cells and their cell surface molecules Ya-Ting Han University College London Institute of Child Health A thesis submitted for the degree of Philosophiae Doctor For the incredible cells that drive me here. ii Acknowledgements I would like to firstly thank my supervisor Prof. Jane Sowden for her consistent support, encouragement and advice throughout my PhD. I still remember when I just started my PhD and wanted some dendritic cells in a control experiment for some even not so exciting markers, Jane instantly contacted her colleagues to provide me these cells. Cases as such are countless. I have been encouraged to develop my own research ideas and Jane has always been supporting. It is through all these that I confidently and happily conducted my studies here. I am very happy that I chose the right supervisor. Thank you, Jane! I would also like to thank my secondary supervisor Prof. Robin Ali for his encouragements throughout, Dr. Janny Morgan for her advice during my PhD upgrade, Prof. Andy Copp, Prof. David Muller, Dr. Kenth Gustafsson, Dr. Andy Stoker, Dr. Juan-Pedro Martinez-Barbera, and Dr. Patrizia Ferretti for helpful discussion and advices. Thanks to Dr. Kevin Mills and Dr. Wendy Heywood for their supports with mass spectrometry, especially Wendy for her unlimited kind and generous help during all my time with mass spectrometry. Thanks to Dan who helped and advised me in molecular cloning. Thanks to Rachael who performed all the injections for cell transplantation. Thanks to Jorn who showed me the techniques when I just entered the lab and helped me with my first cell transplantation.
    [Show full text]
  • Inbreeding and Inbreeding Depression in Linebred Beef Cattle (PDF)
    INBREEDING AND INBREEDING DEPRESSION IN LINEBRED BEEF CATTLE by Jordan Kelley Hieber A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Animal Science MONTANA STATE UNIVERSITY Bozeman, Montana April 2020 ©COPYRIGHT by Jordan Kelley Hieber 2020 All Rights Reserved ii DEDICATION To my family and close friends for their continuous support and countless words of encouragement. To my great papa, great grandma, and grandpa who I know are watching over me and cheering me on from above. ii ACKNOWLEDGEMENTS First and foremost, I must thank Drs. Jennifer Thomson, Jane Ann Boles, and Rachel Endecott for their constant support and friendship since I moved to Montana, and Dr. Elhamidi Hay for his expertise and being a member of my committee. This project also would not have been possible without the funding provided by the Montana State University Montana Agricultural Experiment Station, the United States Department of Agriculture – Agriculture Research Service, and the Montana State University Graduate School. I would like to thank those at the Northern Agricultural Research Center who helped collect data and work cows for my project, especially Dr. Darrin Boss, Julia Dafoe, and Cory Parsons. To my academic “siblings” and fellow graduate students, thank you for all the laughs, support, and shoulders to lean on. I also cannot forget all the amazing faculty and staff within ABB that have provided guidance and given countless words of encouragement. I owe the largest thank you to my support system over the last four years, my family and friends. Thank you for providing an endless amount of support and reassurance throughout this adventure, I love you all! To my boyfriend, thank you for all of your support! You may be a recent addition to my life, but you have provided limitless encouragement.
    [Show full text]
  • Toll-Like Receptor As a Potential Biomarker in Renal Diseases
    International Journal of Molecular Sciences Review Toll-Like Receptor as a Potential Biomarker in Renal Diseases Sebastian Mertowski 1,* , Paulina Lipa 2 , Izabela Morawska 1 , Paulina Nied´zwiedzka-Rystwej 3,* , Dominika B˛ebnowska 3 , Rafał Hrynkiewicz 3 , Ewelina Grywalska 1,* , Jacek Roli ´nski 1 and Wojciech Załuska 4 1 Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] (I.M.); [email protected] (J.R.) 2 Department of Genetics and Microbiology, Institute of Microbiology and Biotechnology, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19 St., 20-033 Lublin, Poland; [email protected] 3 Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; [email protected] (D.B.); [email protected] (R.H.) 4 Department of Nephrology, Medical University of Lublin, 20-954 Lublin, Poland; [email protected] * Correspondence: [email protected] (S.M.); [email protected] (P.N.-R.); [email protected] (E.G.) Received: 30 August 2020; Accepted: 11 September 2020; Published: 13 September 2020 Abstract: One of the major challenges faced by modern nephrology is the identification of biomarkers associated with histopathological patterns or defined pathogenic mechanisms that may assist in the non-invasive diagnosis of kidney disease, particularly glomerulopathy. The identification of such molecules may allow prognostic subgroups to be established based on the type of disease, thereby predicting response to treatment or disease relapse. Advances in understanding the pathogenesis of diseases, such as membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, IgA (immunoglobulin A) nephropathy, and diabetic nephropathy, along with the progressive development and standardization of plasma and urine proteomics techniques, have facilitated the identification of an increasing number of molecules that may be useful for these purposes.
    [Show full text]